Negishi cross-coupling of organotellurium compounds: Synthesis of biaryls, aryl-, and diaryl acetylenes

Article abstract of DOI:10.1016/j.tetlet.2011.06.025

A functional group tolerant palladium-catalyzed Negishi coupling of diaryl tellurides with organozinc has been developed. This methodology permits efficient preparation of biaryls, aryl acetylenes and diaryl acetylenes in moderate to good yields. A preliminary study to gain further insight into the reaction was performed using in situ ReactIR technology.

Full text of DOI:10.1016/j.tetlet.2011.06.025

Tetrahedron Letters 52 (2011) 4398–4401
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Negishi cross-coupling of organotellurium compounds: synthesis of biaryls,
aryl-, and diaryl acetylenes
Hélio A. Stefani a, , Jesus M. Pena a, Flávia Manarin a, Rômulo A. Ando b, Daiana M. Leal a, Nicola Petragnani b
⇑
a Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil
b Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A functional group tolerant palladium-catalyzed Negishi coupling of diaryl tellurides with organozinc has
been developed. This methodology permits efficient preparation of biaryls, aryl acetylenes and diaryl
acetylenes in moderate to good yields. A preliminary study to gain further insight into the reaction
was performed using in situ ReactIR technology.
Received 20 May 2011
Revised 2 June 2011
Accepted 7 June 2011
Available online 21 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tellurium
Diaryl tellurides
Zinc
Negishi reaction
Aromatic rings
R
OH
H
Introduction
OH
OH
O
S
N
N
O
Carbon–carbon bond formation is a major focus of research in
organic synthesis. Tools for making such bonds are indispensable
for the construction of complex molecules and intense efforts are
continuously directed toward developing novel and selective
bond-forming reactions.1
HO
HO
N
OH
N
O
OH
OH
N
S
OMe
O
S
N
MeO
S
O
N
O
N
H
O
N
O
H
H
O
MeO
MeO
N
HO
HO
H
The transition metal-catalyzed cross-coupling reaction of orga-
nometallics is a methodology widely used by many in the chemical
community to produce products prevalent in pharmaceuticals, li-
gands, and materials. Extensive research has focused on a variety
of ways to form C–C bonds using transition metal catalysts.2
The palladium-catalyzed Negishi cross-coupling, the reaction of
aryl and vinyl halides/triflates with organozinc reagents, repre-
sents a powerful tool for the formation of carbon–carbon bonds
in view of the ready availability and high functional group compat-
ibility of organozinc compounds.3 Some particular examples of this
type of cross-coupling reaction has been provided recently by a
number of authors in the synthesis of tylocrebrine,4 salmoche-
lines,5 amythiamicin C and D,6 just to mention a few (Fig. 1).
On the other hand, organotellurium compounds have attained
remarkable interest as synthons and intermediates in synthetic
organic chemistry.7 In the current decade, organotellurium
compounds have been identified as alternatives to halogens as
electrophilic partners in some palladium-catalyzed cross-coupling
N
N
N
O
S
S
N
H
O
Tylocrebine
Salmochelin S1
Amythiamicin
Figure 1. Structure of amithiamicin, tylocrebine and Salmocheline S1.
reactions, such as Heck,8 Negishi,9 Sonogashira10 and Suzuki–
Miyaura.11 Recently, we have reported the use of some organotel-
lurium compounds in
a Suzuki–Miyaura reaction employing
potassium organotrifluoroborate salts as nucleophilic partners.11
Until now, only a few studies on the coupling reaction of organo-
zinc with organotellurides have been described.12
Herein, we report our success in accomplishing a sp2–sp2 and
sp2–sp Negishi coupling reaction between diaryl tellurides and
organozinc reagents.
Results and discussion
The diaryltelluride starting materials were prepared in good to
excellent yields through the reaction of diarylditellurides13 with
⇑
Corresponding author.
E-mail address: hstefani@usp.br (H.A. Stefani).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.025

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4398–4401
4399
R
BF3K
Cu(OAc)2 (1%)/bpy (1%)
DMSO/H2O, 110ºC
12h, air
Te
Te
R
+
R
Te
R
R
1a-f
Te
2
Te
2
H3CO
Te
2
F
Te
2
Cl
Te
2
Te
S
2
1a-85%
1c-90%
1d-85%
1b-65%
1e-80%
1f-70%
Scheme 1.
Table 1
Br
Screening of the catalyst in the Negishi reaction of diphenyltelluride with
(4-methoxyphenyl)zinc(II) chloride
R1
i) n-BuLi, THF, -78ºC (1h)
ii) ZnCl2, THF, -78ºC (1h)
R-ZnCl
or
"Pd", "Cu"
OMe
+ MeO
ZnCl
Te
30 min., r.t.
THF, reflux, N2
12h
H
R2
2b
1a
R = aryl or alkynyl
Entry
Pd Catalyst (10 mol %)
‘Cu’ (equiv)
Yield (%)
Scheme 2.
1
2
3
4
5
6
7
8
Pd(PEPPSI)
PdCl2
Pd(OAc)2
Pd(PPh3)4
PdCl2(PPh3)2
Pd2(dba)3
No catalyst
PdCl2(dppf)ÁCH2Cl2
PdCl2(dppf)ÁCH2Cl2
PdCl2(dppf)ÁCH2Cl2
PdCl2(dppf)ÁCH2Cl2
PdCl2(dppf)ÁCH2Cl2
PdCl2(dppf)ÁCH2Cl2
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
—
CuI (1)
CuI (0.5)
Cu(OAc)2 (1)
CuCN (1)
CuCl (1)
CuSO4Á5H2O (1)
40
29
15
45
83
23
—
88
34
29
38
56
27
potassium aryltrifluoroborate salts bearing electron-withdrawing,
electron-donating, and neutral substituents, using catalytic
a
amount of Cu(OAc)2 and bypyridine in DMSO/H2O in moderate to
good yields14,15 (65–90%) (Scheme 1).
Following the Buchwald procedure,16 the organozinc reagent
was prepared in situ from corresponding aryl bromides or arylalky-
nyl acetylene in dry THF. The resulting solution was cooled to
À78 °C, then n-butyllithium was added dropwise via a syringe
through the septum, and the resulting solution was stirred at
À78 °C for 1 h. ZnCl2 was added in one portion by removal of the
septum (Scheme 2).
9
10
12
13
14
product yield and reaction rate (88% and 83%, respectively).
Pd(OAc)2, PdCl2, Pd2(dba)3, Pd(PEPPSI), Pd(PPh3)4 were found to
be less efficient, affording the coupled product in 15–45% yield.
No reaction took place in the absence of a catalyst (Table 1).
With the substrates in hand, we began our investigation on the
optimization of the Pd source, additives and solvents.
Of the various palladium catalysts tested, PdCl2(dppf)ÁCH2Cl2
and PdCl2(PPh3)2 proved to be most effective in terms of the
Table 2
Negishi cross-coupling reaction of diaryltellurides and organozinc reagents
ZnCl
R2
ZnCl
3 equiv
R1
3 equiv
R2
2
Te
2
PdCl2(dppf).CH2Cl2
CuI (1 mmol)
THF, reflux
12h
R
R
PdCl2(dppf).CH2Cl2
CuI (1 mmol)
THF, reflux
12h
R1
R
R
2a-e
3a-e
1a-f
R, R1 = H, F, Cl, OMe
R2 = aryl, alkyl
Entry
1
Telluride
Organozinc
Product/Yield (%)
OMe
Te
2
O
ZnCl
ZnCl
ZnCl
2a-88%
1a
F
Te
O
F
OMe
OMe
2
3
4
2
2b-67%
1b
Te
O
2
2c-72%
2d-32%
1c
1c
Te
ZnCl
2
(continued on next page)

4400
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4398–4401
Table 2 (continued)
Entry
Telluride
Organozinc
Product/Yield (%)
OMe
S
Te
O
ZnCl
S
2
5
6
1f
2e-47%
MeO
Te
ZnCl
2
1d
3a-59%
MeO
MeO
MeO
1a
Te
2
7
8
9
ZnCl
3b-87%
1d
Te
2
ZnCl
ZnCl
3c-90%
Te
2
3d-72%
1c
Cl
Te
2
ZnCl
10
3e-67%
1e
Cl
Catalyst loading was also studied, indicating that the use of
5 mol % of PdCl2(dppf)ÁCH2Cl2 was not very effective, affording
25% yield of the desired cross-coupled product in addition to a rel-
atively small amount (>10%) of the homocoupled product. Once
PdCl2(dppf)ÁCH2Cl2 was identified as the best catalyst, the influ-
ence of the copper salt employed on the cross-coupling reaction
was examined. The next step, as shown in Table 1 (entries 8–14),
was the determination of the best copper additive. Different cop-
per(I) and copper(II) species were tested in the coupling reaction,
displaying poor to high yields; the best result was obtained using
CuI (1 mmol), giving the desired product in very good yield
(Table 1, entry 8).
The highest yield was achieved using THF as the solvent, affording
the cross-coupled product in 88% yield.
Thus, it was deemed that the optimum conditions for the cross-
coupling reaction of interest involved the use of organotellurides
(0.5 mmol), organozinc reagents (3.0 mmol), PdCl2(dppf)ÁCH2Cl2
(10 mol %), and CuI (1.0 mmol) in THF solvent at reflux tempera-
ture (Table 2). Having established the viability of the presented
methodology, the general applicability as well as the reactivity of
various organozinc and aryl tellurides was also tested17 (Table 2).
The reaction demonstrated tolerance to common functional
groups in aromatic rings like fluorine, methyl and methoxy with
yields ranging from 32% to 88% (Table 2, entries 1–4). In the case
of thiophene, the yield was very modest, only 47% (Table 2, entry
5). On the other hand, the aryl acetylenes (Table 2, entries 6–10)
were accomplished in moderate to good yields.
Copper loading was also analyzed. When the amount of CuI was
dropped to 0.5 equiv, the product was formed in only 34% yield
(Table 1, entry 9).
The influence of the reaction solvent was also investigated. The
reaction occurred in poor to moderate yields in acetonitrile, DME
and THF/DCM, giving the biarylic product in 46%, 63% and 66%
yield, using PdCl2(dppf)CH2Cl2 as the catalyst with copper iodide.
In order to gain further insight into the reaction of interest,
in situ ReactIR spectroscopy18,19 was employed to monitor the con-
version of diphenyltelluride 1a–2a. As can be observed in Figure 2,
after the addition of diarylzinc to the diphenyltelluride, there is a
rapid increase of a band at 1248 cmÀ1 that remains constant few
minutes later, indicating that the reaction occurs quite fast. This in-
tense band can be assigned to a vibrational mode involving the ring
mode /(14) and the methoxy group stretching, m(C–O). A detailed
IR characterization was done for both the reactant and the product
and to complement the vibrational assignment, density functional
theory (DFT) calculations were performed for both species (the
experimental and theoretical IR spectra, as well as the vibrational
assignments are available in the Supplementary data).
Conclusion
The methodology was effective for obtaining asymmetric biaryl,
biaryl acetylene and aryl acetylene compounds in moderate yields
employing Negishi reaction conditions and symmetric diaryl tellu-
rides catalyzed by palladium and copper. Also, the reaction allows
the transference of both aromatic rings linked to tellurium atom.
A preliminary study to gain further insight into the reaction was
performed using in situ ReactIR technology. Further studies on this
methodology and the mechanism reaction are currently ongoing in
our laboratory and will be reported in due course.
Figure 2. Reaction course (Table 2, entry 1) followed by in situ IR spectroscopy. The
structures represented are the optimized geometries of the reactant and the
product obtained by DFT calculations.

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4398–4401
4401
C. M. P.; Zeni, G.; Gomes, M., Jr. Tetrahedron Lett. 2005, 46, 563; (c) Kang, S.-K.;
Hong, Y.-T.; Kim, D. H.; Lee, S.-H. J. Chem. Res. 2001, 283.
Acknowledgments
12. (a) Dabdoub, M. J.; Dabdoub, V. B.; Marino, J. P. Tetrahedron Lett. 2000, 41, 433;
(b) Dabdoub, M. J.; Dabdoub, V. B.; Marino, J. P. Tetrahedron Lett. 2000, 41, 437;
(c) Oliveira, J. M.; Zeni, G.; Malvestiti, I.; Menezes, P. H. Tetrahedron Lett. 2006,
47, 8183.
13. Alves, D.; Pena, J. M.; Vieira, A. S.; Botteselle, G. V.; Guadagnin, R. C.; Stefani, H.
A. J. Braz. Chem. Soc. 2009, 20, 988.
The authors would like to acknowledge Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq 300.613/2007–
5) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FA-
PESP 07/59404–2, 10/15677–8) for their financial support.
14. Stefani, H. A.; Pena, J. M.; Gueogjian, K.; Petragnani, N.; Vaz, B. G.; Eberlin, M. N.
Tetrahedron Lett. 2009, 50, 5589.
15. General procedure for the cross-coupling reaction of diaryl ditellurides with
Supplementary data
potassium aryltrifluoroborates. To
a round-bottom flask containing diaryl
ditelluride (0.25 mmol), potassium aryltrifluoroborate salt (0.5 mmol),
Cu(OAc)2 (1 mol %) and bpy (1 mol %), DMSO (1 mL) and H2O (0.5 mL) were
added. The reaction mixture was allowed to stir at reflux for 12 h. After this
time, the solution was cooled to room temperature, diluted with
dichloromethane (20 mL) and washed with saturated aqueous NH4Cl
(3 Â 20 mL). The organic phase was separated, dried over MgSO4 and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel using ethyl acetate/hexane as the eluent. Bis-
(p-tolyl)-telluride (1c). The product was obtained in 94% yield. NMR 1H (CDCl3,
300 MHz) d (ppm): 7,57 (d, J = 7,7 Hz, 4H), 7,01 (d, J = 7,7 Hz, 4H), 2,33 (s, 6H).
NMR 13C (CDCl3, 75 MHz) d (ppm): 139,2(2C), 136,9 (4C), 131,4 (4C), 110,7
(2C), 22,0. ESI MS (relative intensity) m/z (%): 312 (34), 182 (100), 167 (72), 91
(59), 65 (36). HRMS calcd C14H14Te: 312,0157. found: 312,0169.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.025.
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